Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as H3 antagonists

ABSTRACT

The invention features methods of using pharmaceutically-active 2- or 3-aryl substituted imidazopyridines and derivatives.

Cross-Reference to Related Applications

[0001] This application claims priority from U.S. ProvisionalApplication Serial Number 60/194,071, filed on Mar. 31, 2000, our DocketNumber ORT-1 158 and U.S. Provisional Application Serial Number60/______,______, filed on Feb. 28, 2001, our Docket Number ORT-1369.

FIELD OF THE INVENTION

[0002] The invention relates to methods of using pharmaceutically-activefused heterobicyclic compounds to treat or prevent disorders andconditions mediated by the histamine H₃ receptor.

BACKGROUND

[0003] The histamine H₃ receptor is located as a presynapticautoreceptor in the central nervous system and as a presynapticheteroreceptor on serotonergic, noradrenergic, dopaminergic, andcholinergic neurons. The histamine H₃ receptor is also locatedperipherally in tissues such as vascular smooth muscle cells.

[0004] Proposed uses of histamine H₃ antagonists include the treatmentor prevention of dementia, Alzheimer's disease (Panula et al. Abstr.Society Neuroscience, 1995, 21:1977), epilepsy (Yokoyama et al. Eur. J.Pharmacol., 1993, 234:129), sleep/wake disorders (Lin etal., Br. Res.,1990, 523, 325; Monti et al., Eur. J. Pharmacol., 1991,205, 283)including narcolepsy, insomnia, and jet lag, eating disorders (Machidoriet al. Brain Research, 1992, 590:180), motion sickness, vertigo,attention deficit hyperactivity disorder, learning and memory disorders(Barnes et al. Abstr. Society Neuroscience, 1993,19:1813), schizophrenia(Schlickeret al. Naunyn Schmiedeberg's Arch. Pharmacol., 1996, 353:325),and sequelae associated with post-ischemic reperfusion and hypertension(Imamura et al., J. PharmacoL Expt. Ther., 1994, 271,1259). H₃antagonists are also useful to treat or prevent neurogenic inflammationsuch as migraine (McLeod et al., Abstr. Society Neuroscience, 1996, 22,2010), asthma (Ichinose et al., Eur. J. Pharmacol., 989,174, 49),obesity, allergic rhinitis, substance abuse, bipolar disorders, manicdisorders, and depression. Histamine H₃ antagonists alone or incombination with a histamine H₁ antagonist are believed to be useful inthe treatment of upper airway allergic response or allergic rhinitis(see, e.g., U.S. Pat. Nos. 5,217,986, 5,352,707, and 5,869,479).

[0005] As noted, the prior art related to histamine H₃ ligands wascomprehensively reviewed recently (“The Histamine H ₃ Receptor-A Targetfor New Drugs”, Leurs, R., and Timmerman, H., (Editors), Elsevier,1998). Within this reference the medicinal chemistry of histamine H₃agonists and antagonists was reviewed (see Krause et al. and Phillips etal., respectively). Thus the importance of an imidazole moietycontaining only a single substitution in the 4 position was notedtogether with the deleterious effects of additional substitution onactivity. Particularly methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity.

[0006] More recently several publications have described histamine H₃ligands that do not contain an imidazole moiety. Examples includeGanellin et al Arch. Pharm. (Weinheim,Ger.) 1998, 331, 395; Walczynskiet al Arch. Pharm. (Weinheim,Ger.) 1999, 332, 389; Walczynski et alFarmaco 1999, 684; Linney et al J. Med. Chem. 2000, 2362; U.S. Pat. No.5,352,707; PCT Application WO99/42458, published Aug. 26,1999; andEuropean Patent Application 0978512, published on Feb. 9, 2000.

SUMMARY OF THE INVENTION

[0007] The invention features the use of the compounds of formula (I)for the treatment and/or prevention of diseases and conditions mediatedby the histamine 3 (H₃) receptor.

[0008] R is O or S;

[0009] R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, or l;

[0010] R₂ and R₃ are H or —O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃is H and the other is —O—(CH₂)_(m)—NR₄R₅, when R₃ is —O—(CH₂)_(m)—NR₄R₅,R₂ is independently H, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

[0011] R₄ and R₅ are the same or different, and are C₁₋₅ alkyl, Ccycloalkyl, benzyl, benzyl substituted by C₁₋₄ alkyl, C 14 alkoxy, Br,Cl, l, or R₄ and R₅ together with N are piperidyl, pyrrolidyl,imidazolyl, or N- substituted piperazyl, wherein the substituent is C₁₋₄alkyl, phenyl, or phenyl substituted with C₁₋₃ alkoxy; n is 0 or 1; m is2-6; with the provisos that when at least one of R and R₁ is Ar; andboth of R and R₁ are not Ar;

[0012] or a pharmaceutically acceptable salt, ester, or amide thereof.

[0013] Many of the compounds are disclosed generically in U.S. Pat. No.4,861,897. These compounds were first identified as having antisecretoryproperties. Additional features of the invention are disclosed in thefollowing description and examples, and in the appended claims.

DETAILED DESCRIPTION

[0014] The invention features pharmaceutically active phenyl-substitutedimidazopyridines and methods of making and using them. The descriptionis organized as follows:

[0015] A. Terms

[0016] B. Compounds

[0017] C. Synthetic Methods

[0018] D. Uses

[0019] E. Synthetic Chemical Examples

[0020] F. Biological Examples

[0021] G. Other Embodiments

[0022] H. claims

[0023] A. Terms

[0024] The following terms are defined below and by their usagethroughout this disclosure.

[0025] “Alkyl” includes straight chain and branched hydrocarbons with atleast one hydrogen removed to form a radical group. Alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, andso on.

[0026] “Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on.

[0027] “halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably fluoro or chloro.

[0028] “patient” or “subject” includes mammals such as humans andanimals (dogs, cats, horses, rats, rabbits, mice, non-human primates) inneed of observation, experiment, treatment or prevention in connectionwith the relevant disease or condition. Preferably, the patient is ahuman.

[0029] “composition” includes a product comprising the specifiedingredients in the specified amounts as well as any product whichresults directly or indirectly from combinations of the specifiedingredients in the specified amounts.

[0030] Concerning the various radicals in this disclosure and in theclaims, two general remarks are made. The first remark concerns valency.As with all hydrocarbon radicals, whether saturated, unsaturated oraromatic, and whether or not cyclic, straight chain, or branched, andalso similarly with all heterocyclic radicals, each radical includessubstituted radicals of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context of the claims. Thecontext will indicate that the substituent is an alkylene or hydrocarbonradical with at least two hydrogen atoms removed (bivalent) or morehydrogen atoms removed (multivalent).

[0031] Second, radicals or structure fragments as defined herein areunderstood to include substituted radicals or structure fragments. Using“alkyl” as an example, “alkyl” should be understood to includesubstituted alkyl having one or more substitutions, such as between 1and 5, 1 and 3, or 2 and 4 substituents. The substituents may be thesame (dihydroxy, dimethyl), similar (chlorofluoro), or different(chlorobenzyl- or aminomethyl-substituted). Examples of substitutedalkyl include haloalkyl (such as fluoromethyl, chloromethyl,difluoromethyl, perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl),hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, and so on.

[0032] B. Compounds

[0033] One aspect of the invention features compounds of formula (I) asdescribed in the Summary section above.

[0034] Preferred compounds of formula (I) include those compoundswherein: (a) R₂ is H; (b) R₃ is H; (c) R is O; (d) R₁ is H; (e) R is S;(f) n is 1; (g) n is 0; (h) NR₄R₅ is a cyclic radical; (i) (h) whereinsaid cyclic radical is piperidyl or pyrrolinyl; 0) each of R₄ and R₅ isindependently selected from ethyl, propyl, isopropyl, and butyl,including n-butyl, sec-butyl, tert-butyl, and isobutyl; (k) m is 2, 3,or 4, and more preferably wherein m is 3 or 4; (l) m is 3; (m) R₁ is H,methyl, methoxy, Br, Cl, or l; (n) R₂ is H, halogen, methyl, or methoxy,and preferably methyl; (o) or combinations thereof.

[0035] Additional preferred compounds include those wherein: R₁ is H,methyl, methoxy, Br, Cl, or l; each of R₄ and R₅ is independentlyselected from ethyl, propyl, isopropyl, and butyl, or together with Nare piperidyl or pyrrolinyl; m is 3 or 4; and each R₂ is H, halogen,methyl, or methoxy.

[0036] Preferred compounds include:(E)-2-[2-(3-dibutylaminopropoxyphenyl)-ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]-phenyl]ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole;and acid addition salts thereof.

[0037] Preferred compounds also include:(E)-2-[2-(4-dibutylaminopropoxy-phenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylamino-butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)-ethenyllbenzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole; andacid addition salts thereof.

[0038] Additional preferred compounds include:(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazoleand(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;and acid addition salts thereof.

[0039] More preferred compounds include:(E)-2-[2-(4-Piperidinopropoxy-phenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]-ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxy-phenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)-ethenyl]benzoxazole; and2-(4-Dipropylaminopropoxyphenyl)benzothiazole and pharmaceuticallyacceptable salts thereof.

[0040] Other examples of compounds, and methods of making them, areprovided in the examples below.

[0041] C. Synthetic Methods

[0042] The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Traditional organic synthetic methodsare described in U.S. Pat. No. 4,861,897, which is incorporated byreference in its entirety. Further guidance is found in ChemicalExamples 1-8 below.

[0043] C. Uses

[0044] According to the invention, the disclosed compounds andcompositions are useful for the amelioration of symptoms associatedwith, the treatment of, and/or the prevention of, the followingconditions and diseases, or symptoms associated with them: dementia,Alzheimer's disease, narcolepsy, eating disorders, motion sickness,vertigo, attention deficit hyperactivity disorder, learning and memorydisorders, schizophrenia, mild cognitive impairment, upper airwayallergic response (allergic rhinitis), insomnia, jet lag, obesity,asthma, neurogenic inflammation, substance abuse, bipolar disorders,manic disorders, and depression. The invention also featurespharmaceutical compositions, which include, without limitation, one ormore of the disclosed compounds, and a pharmaceutically acceptablecarrier or excipient.

[0045] 1. Dosages

[0046] Those skilled in the art will be able to determine, according toknown methods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of symptomsrequiring treatment, and the use of other medications. An effectiveamount means that amount of pharmaceutical reagent (such as a prodrug,metabolic precursor, or active compound) that elicits the biological ormedical response desired. In general, a therapeutically effective amountwill be between 0.01 and 1000 mg/kg per day, preferably between 0.01 and250 mg/kg body weight, and daily dosages will be between 0.50 and 5000mg for an adult subject of normal weight. Capsules, tablets or otherformulations (such as liquids and film-coated tablets) may be of between0.20 and 100 mg, such as 0.20, 0.50, 1, 2, 3, and 10 mg can beadministered according to the disclosed methods.

[0047] 2. Formulations

[0048] Dosage unit forms include tablets, capsules, pills, powders,granules, aqueous and nonaqueous oral solutions and suspensions, andparenteral solutions packaged in containers adapted for subdivision intoindividual doses. Dosage unit forms can also be adapted for variousmethods of administration, including controlled release formulations,such as subcutaneous implants. Administration methods include oral,rectal, parenteral (intravenous, intramuscular, subcutaneous),intracisternal, intravaginal, intraperitoneal, intravesical, local(drops, powders, ointments, gels or cream), and by inhalation (a buccalor nasal spray) as appropriate depending on the overall health andcondition of the patient as determined by a physician or veterinarydoctor.

[0049] Parenteral formulations include pharmaceutically acceptableaqueous or nonaqueous solutions, dispersion, suspensions, emulsions, andsterile powders for the preparation thereof. Examples of carriersinclude water, ethanol, polyols (propylene glycol, polyethylene glycol),vegetable oils, and injectable organic esters such as ethyl oleate.Fluidity can be maintained by the use of a coating such as lecithin, asurfactant, or maintaining appropriate particle size. Carriers for soliddosage forms include (a) fillers or extenders, (b) binders, (c)humectants, (d) disintegrating agents, (e) solution retarders, (f)absorption accelerators, (g) adsorbants, (h) lubricants, (i) bufferingagents, and (j) propellants.

[0050] Compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents; antimicrobial agents suchas parabens, chlorobutanol, phenol, and sorbic acid; isotonic agentssuch as a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

[0051] 3. Combination Therapy

[0052] The present invention also provides compositions and methodsuseful for the treatment of disorders or conditions modulated,preferably antagonized, by the histamine H₃ receptor in combination withcompounds that modulate other receptors including, but not limited to,histamine H₁ and histamine H₂ receptors. The present invention includescompounds and compositions useful in methods of combination therapy forthe treatment of diseases or conditions modulated by the histamine H₃receptor in combination with compounds that are selective serotoninre-uptake inhibitors (SSRIs), such as PROZACTM, or are selectivenorepinephrine uptake inhibitors. Such combination methods include (a)administering the two or more pharmaceutical agents separatelyformulated and at separate times, and (b) administering the two or moreagents simultaneously in a single formulation or in separateformulations administered more or less at the same time. For example,one aspect is a method of treatment comprising administering at leastone histamine H₃ receptor modulating compound disclosed herein andadministering at least one compound selected from a histamine H₁receptor modulating compound, a histamine H₂ receptor modulatingcompound, a selective serotonin reuptake inhibitor (such as PROZAC™), ora selective norepinephrine uptake inhibiting compound.

[0053] 4. Related Compounds

[0054] The invention provides the disclosed compounds and closelyrelated, pharmaceutically acceptable forms of the disclosed compounds,such as salts, esters, amides, acids, hydrates or solvated formsthereof; masked or protected forms; and racemic mixtures, orenantiomerically or optically pure forms.

[0055] Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈, alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di (C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

[0056] The invention also includes disclosed compounds having one ormore functional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., (1999) John Wiley & Sons, NY. Some ofthese masked or protected compounds are pharmaceutically acceptable;others will be useful as intermediates. Synthetic intermediates andprocesses disclosed herein, and minor modifications thereof, are alsowithin the scope of the invention.

[0057] Hydroxyl Protecting Groups

[0058] Protection for the hydroxyl group includes methyl ethers,substituted methyl ethers, substituted ethyl ethers, substitute benzylethers, and silyl ethers.

[0059] Substituted Methyl Ethers

[0060] Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyidimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

[0061] Substituted Ethyl Ethers

[0062] Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

[0063] Substituted Benzyl Ethers

[0064] Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, a-naphthyidiphenylmethyl,p-methoxyphenyidiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

[0065] Silyl Ethers

[0066] Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyidimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

[0067] Esters

[0068] In addition to ethers, a hydroxyl group may be protected as anester. Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P- phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate) Carbonates Examples of carbonateprotecting groups include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

[0069] Assisted Cleavage

[0070] Examples of assisted cleavage include 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

[0071] Miscellaneous Esters

[0072] Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

[0073] Sulfonates

[0074] Examples of sulfonates include sulfate,methanesulfonate(mesylate), benzylsulfonate, and tosylate.

[0075] Protection for 1,2- and 1,3-Diols

[0076] Cyclic Acetals and Ketals

[0077] Examples of cyclic acetals and ketals include methylene,ethylidene, 1-t-butylethylidene, 1-phenylethylidene,(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide(isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene,benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene,3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.

[0078] Cyclic Ortho Esters

[0079] Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, a-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,a-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

[0080] Silyl Derivatives

[0081] Examples of silyl derivatives include di-t-butylsilylene group,and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

[0082] Amino Protecting Groups

[0083] Protection for the amino group includes carbamates, amides, andspecial —NH protective groups.

[0084] Examples of carbamates include methyl and ethyl carbamates,substituted ethyl carbamates, assisted cleavage carbamates, photolyticcleavage carbamates, urea-type derivatives, and miscellaneouscarbamates.

[0085] Carbamates

[0086] Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,1 0-tetrahydrothioxanthyl)]methyl, and4-methoxyphenacyl.

[0087] Substituted Ethyl

[0088] Examples of substituted ethyl carbamates include2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,1,1-dimethyl-2,2- dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl,2-(2′- and 4′-pyridyl) ethyl, 2-(N,N-dicycl ohexylcarboxamido)ethyl,t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylall yl, cinnamyl,4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl,p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl,2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl anddiphenylmethyl.

[0089] Assisted Cleavage

[0090] Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

[0091] Photolytic Cleavage

[0092] Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

[0093] Urea-type Derivatives

[0094] Examples of urea-type derivatives includephenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl, and N′-phenylaminothiocarbonyl.

[0095] Miscellaneous Carbamates

[0096] Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropyl methyl, p-decyloxybenzyl, diisopropyl methyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

[0097] Examples of amides include:

[0098] Amides

[0099] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

[0100] Assisted Cleavage

[0101] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

[0102] Cyclic Imide Derivatives

[0103] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

[0104] Special-NH Protective Groups

[0105] Examples of special NH protective groups include

[0106] N-Alkyl and N-Aryl Amines

[0107] N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3,-acetoxypropyl, N-(1-isopropyl4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

[0108] Imine Derivatives

[0109] N-1,1-dimethylthiomethylene, N-benzylidene,N-p-methoxybenzylidene, N-diphenylmethylene,N-[(2-pyridyl)mesityl]methylene, and N-(N′,N′-dimethylaminomethylene).

[0110] Protection for the Carbonyl Group

[0111] Acyclic Acetals and Ketals

[0112] Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

[0113] Cyclic Acetals and Ketals

[0114] Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,0,O′-phenylenedioxy and 1 ,5-dihydro-3H-2,4-benzodioxepin.

[0115] Acyclic Dithio Acetals and Ketals

[0116] Examples of acyclic dithio acetals and ketals includeS,S′-dimethyl, S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl,S,S′-diphenyl, S,S′-dibenzyl and S,S′-diacetyl.

[0117] Cyclic Dithio Acetals and Ketals

[0118] Examples of cyclic dithio acetals and ketals include1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

[0119] Acyclic Monothio Acetals and Ketals

[0120] Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl andO-methyl-S-2-(methylthio)ethyl.

[0121] Cyclic Monothio Acetals and Ketals

[0122] Examples of cyclic monothio acetals and ketals include1,3-oxathiolanes.

[0123] Miscellaneous Derivatives

[0124] O-Substituted Cyanohydrins

[0125] Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

[0126] Substituted Hydrazones

[0127] Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

[0128] Oxime Derivatives

[0129] Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

[0130] Imines

[0131] Substituted Methylene Derivatives, Cyclic Derivatives

[0132] Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hyd roxyalkyl)imidazoles, N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamineadducts, and methylaluminumbis(2,6-di-t-butyl4-methylphenoxide)(MAD)complex.

[0133] Monoprotection of Dicarbonyl Compounds

[0134] Selective Protection Of α-and β-Diketones

[0135] Examples of selective protection of α-and β-diketones includeenamines, enol acetates, enol ethers, methyl, ethyl, 1-butyl,piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl,S-butyl, and trimethylsilyl.

[0136] Cyclic Ketals, Monothio and Dithio Ketals

[0137] Examples of cyclic ketals, monothio and dithio ketals includebismethylenedioxy derivatives and tetramethylbismethylenedioxyderivatives.

[0138] Protection for the Carboxyl Group

[0139] Esters

[0140] Examples of esters include the following.

[0141] Substituted Methyl Esters

[0142] Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, β-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

[0143] 2-Substituted Ethyl Esters

[0144] Examples of 2-substituted ethyl esters include2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl,2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

[0145] Substituted Benzyl Esters

[0146] Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

[0147] Silyl Esters

[0148] Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, 1-propyidimethylsilyl, phenyidimethylsilyl anddi-t-butylmethylsilyl.

[0149] Activated Esters

[0150] Examples of activated esters include thiols.

[0151] Miscellaneous Derivatives

[0152] Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

[0153] Stannyl Esters

[0154] Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

[0155] Amides and Hydrazides

[0156] Amides

[0157] Examples of amides include N,N-dimethyl, pyrrolidinyl,piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, andp-P-benzenesulfonamides.

[0158] Hydrazides

[0159] Examples of hydrazides include N-phenyl and N,N′-diisopropylhydrazides.

[0160] D. Synthetic Chemical Examples

[0161] Additional experimental descriptions of the compounds of theinvention are found in the Examples of U.S. Pat. No. 4,861,897,incorporated herein by reference in its entirety. Examples 3, 4, 6, 7,8, and 9 below correspond to Examples 1,2, 13, 7, 8, and 14 of the '897patent, respectively, and are provided as general guidance.

EXAMPLE 1 (E)-2-[2-(4-Dibutylaminopropoxyphenyl)ethenyl]benzoxazole

[0162] To a suspension of sodium hydride (50% in oil, 3.9 g, 82 mmol) indimethylformamide (100 ml) was added p-hydroxybenzaldehyde (5.0 g, 41mmol). The mixture was stirred at room temperature under an atmosphereof nitrogen for one hour, then treated dropwise with1-bromo-3-chloropropane (8.1 ml, 82 mmol). The mixture was stirred atroom temperature for 12 hours, quenched with methanol and filteredthrough Celite. The filtrate was dissolved in diethyl ether (500 ml),washed with water (3×200 ml) and dried over Na₂ SO₄. The ether layer wasconcentrated to give 6.1 g (80% yield) of 4-chloropropoxybenzaldehyde asa yellow liquid. ¹H NMR (CDCl₃): δ 9.95 (s, 1H), 7.85 (d, J=8.1 Hz, 2H),7.01 (d, J=8.1 Hz, 2H), 4.21 (t, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 1.26(m, 2H).

[0163] To a solution of this product (5.0 g, 25 mmol) and2-methylbenzoxazole (3.1 ml, 25 mmol) in dimethylsulfoxide (25 ml) wasadded a 50% aqueous sodium hydroxide solution (15 ml). The solution wasstirred at room temperature for 24 hours, diluted with ice water (1 L),and the resulting precipitate was collected by filtration. Theprecipitate was washed with water and dried in vacuo to give(E)-2-[2-(4-chloropropoxyphenyl)ethenyl]benzoxazole (C) (6.4 g, 79%yield) as a yellow solid, mp 82°-83° C. IR(KBr): 1600 cm⁻¹ MS: 313(M⁺).¹H NMR (CDCl₃): δ 7.88-6.79 (m, 10H), 4.19 (t, J=5 Hz, 2H), 3.79 (t, J=5Hz, 2H), 2.31 (m, 2H).

[0164] Theor. C₁₈H₁₆ NO₂ Cl: C, 68.90; H, 5.14; N, 4.46. Found: C,69.20; H, 5.46; N, 4.27.

[0165] A solution of this product (6.0 g, 19 mmol) in 60 ml ofdibutylamine was heated to 150° C. for 12 hours. The excess dibutylaminewas removed by distillation and the resulting oil was purified by flashchromatography (SiGel, 9:1 CHCl₃ -MeOH) to give 5.8 g (75% yield) of thefree base of the title compound. The HCl salt was prepared by theaddition of concentrated hydrochloric acid to a solution of the freebase in methanol, concentrated, and recrystallized from acetone to givethe HCl salt of the title compound as a yellow solid, mp 153°-154° C.IR(KBr): 3400,1595 cm⁻¹ MS: 406(MH⁺). ¹H NMR (CDCl₃): δ 7.99-6.81 (m,10H), 4.15 (t, J=5 Hz, 2H), 3.09 (m, 6H), 2.44 (m, 2H), 1.99-0.87 (m,16H).

[0166] Theor. C₂₆H.₃₄ N₂ O₂.HCl.1/2 H₂O: C, 69.08; H, 8.03; N, 6.19.Found: C, 68.89; H, 7.92; N, 6.24.

EXAMPLE 2 (E)-2-[2-(4-Dibutylaminopropoxyphenyl)ethenyl]benzothiazole

[0167] The title compound was prepared in accordance with Example 1starting with 4-chloropropoxybenzaldehyde (17.0 g, 86 mmol) and using2-methylbenzothiazole (11 ml, 86 mmol) in place of 2-methylbenzoxazoleto give 25.0 g (89% yield) of(E)-2-[2-(4-chloropropoxyphenyl)ethenyl]benzothiazole (F) as a yellowsolid, mp 97°-99° C. ¹NMR (CDCl₃): δ 8.15-6.91 (m, 10H), 4.15 (t, J=5.2Hz, 2H), 3.81 (t, J=5.2 Hz, 2H), 2.21 (m, 2H).

[0168] Reaction of this product (10.0 g, 30 mmol) with dibutylamineproduced 8.4 g (66% yield) of the free base of the title compound whichwas converted to the HCl salt, mp 181°-182° C. IR(KBr): 3400, 1595 cm⁻¹MS: 422(M⁺). ¹H NMR (CDCl₃): δ 7.88-6.81 (m, 10H), 4.12 (t, J=5.3 Hz,2H), 3.02-2.59 (m, 6H), 2.25-0.84 (m, 16H).

[0169] Theor. C₂₆H₃₄ N₂ OS.2HCl.2H₂ O: C, 58.75; H, 7.58; N, 6.10.Found: C, 58.52; H, 7.14; N, 5.26.

EXAMPLE 3

[0170]

(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole K_(i)=15 nM

[0171] The procedure of Example 2 was followed starting with (F) ofExample 2 (3.0 g, 9.8 mmol) and using piperidine in place ofdibutylamine to produce 1.9 g (51% yield) of the free base of the namedcompound which was converted to the HCl salt, mp 215°-217° C. IR(KBr):3400,1595 cm⁻¹. MS: 379(MH⁺). ¹H NMR (CD₃ OD): δ 7.64-6.48 (m, 10H),3.72 (t, J=5.2 Hz, 2H), 2.65 (m, 6H), 1.98 (m, 2H), 1.32 (m, 6H).

[0172] Theor. C₂₃H₂₆ N₂ OS.1HCl.3/2H₂ O: C, 62.49; H, 6.84; N, 6.34.Found: C, 62.53; H, 6.94; N, 6.26.

EXAMPLE 4

[0173]

(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole K_(i)=13 nM

[0174] The procedure of Example 1 was followed starting with (C) ofExample 1 (2.0 g, 6.4 mmol) and using piperidine in place ofdibutylamine to produce 1.1 g, (41% yield) of the named compound as theHCl salt, mp 127°-128° C. IR(KBr): 3400,1600 cm⁻¹. MS: 363(MH⁺). ¹H NMR(CD₃ OD): δ 7.89-6.81 (m, 10H), 4.24 (t, J=5.5 Hz, 2H), 2.65 (m, 6H),1.75 (m, 8H).

[0175] Theor. C₂₃H₂₆ N₂ O₂.HCl.H₂ O: C, 66.26; H, 6.77; N, 6.72. Found:C, 66.01; H, 6.92; N, 6.98.

EXAMPLE 5 (E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole

[0176] The procedure of Example 1 was followed withp-hydroxybenzaldehyde (5.0 g, 41 mmol) and using 1-bromo-4-chlorobutane(9.5 ml, 82 mmol) in place of 1-bromo-3-chloropropane to give 8.9 g (97%yield) of 4-chlorobutoxy-benzaldehyde. ¹H NMR (CDCl₃) δ 9.85 (s, 1H),7.82 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H),3.59 (t, J=5.3 Hz, 2H), 1.91 (m, 4H).

[0177] Condensation of this product (4.0 g, 19 mmol) with2-methylbenzoxazole (2.3 ml, 19 mmol) gave(E)-2-[2-(4-chlorobutoxyphenyl)ethenyl]benzoxazole (D) (4.5 g, 72%yield) as an off-white solid, mp 92°-93° C. ¹H NMR (CDCl₃): δ 7.88-6.81(m, 1OH), 4.08 (t, J=5.1 Hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 2.55 (m, 4H).

[0178] Reaction of this product (3.0 g, 9.1 mmol) with dibutylamineproduced the named compound (0.4 g, 11% yield) which was converted tothe HCl salt, mp 172°-174° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 421(MH⁺). ¹HNMR (CD₃ OD):δ 7.82-6.85 (m, 10H), 4.02 (t, J=5.2 Hz, 2H), 3.11 (m, 6H),1.98-0.84 (m, 18H).

[0179] Theor. C₂₇H₃₆ N₂ O₂HCl.H₂ O: C, 68.26; H, 8.27; N, 5.6. Found: C,68.31; H, 7.91; N, 5.48.

EXAMPLE 6

[0180]

(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole K_(i)=34 nM

[0181] The title compound was prepared as described in Example 5starting with (D) of Example 5 (2.5 g, 7.6 mmmol) and using piperidinein place of dibutylamine to produce 1.2 g (42% yield) of the titlecompound as the HCl salt, mp 230′-232° C. IR(KBr): 1600 cm⁻¹. MS:377(MH⁺). ¹H NMR (DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H),3.10 (m, 6H), 1.75 (m, 10H).

[0182] Theor. C₂₄H₂₈ N₂ O₂.HCl: C, 69.80; H, 7.08; N, 6.78. Found: C,70.12; H, 7.09; N, 6.93.

EXAMPLE 7

[0183]

(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole K_(i)=48 nM

[0184] The procedure of Example 5 was followed starting with (D) ofExample 5 (2.5 g, 7.6 mmol) and using diethylamine in place ofdibutylamine to produce 0.32 g (12% yield) of the named compound as theHCl salt, mp 219°-220° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 365(MH⁺). ¹H NMR(CDCl₃): δ 8.25-6.82 (m, 10H), 4.02 (t, J=5.4 Hz, 2H), 3.14 (m, 6H),1.99 (m, 4H), 1.36 (m, 6H).

[0185] Theor. C₂₃H₂₈ N₂ O₃.HCl.H₂ O: C, 65.94; H, 7.46; N, 6.69. Found:C, 66.12; H, 7.25; N, 6.57.

[0186] EXAMPLE 8

(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole K_(i)=31 nM

[0187] The title compound was prepared as described in Example 1starting with (C) of Example 1 (2.0 g, 6.4 mmol) and using diethylaminein place of dibutylamine to produce 2.8 g (85% yield) diethylamine inplace of dibutylamine to produce 2.8 g (85% yield) of the title compoundas the HCl salt, mp 225°-226° C. IR(KBr): 1600 cm⁻¹. MS: 351(MH⁺). ¹HNMR (CD₃ OD): δ 7.99-6.81 (m, 10H), 4.24 (t, J=5.7 Hz, 2H), 3.09 (m,6H), 2.44 (m, 2H), 0.87 (m, 6H).

[0188] Theor. C₂₂H₂₆ N₂ O₂.HCl: C, 68.29; H, 7.03; N, 7.24. Found: C,68.34; H, 7.34; N, 6.91.

EXAMPLE 9

[0189]

(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole K_(i)=17 nM

[0190] The title compound was prepared as described in Example 5starting with (D) of Example 5 (3.0 g, 9.1 mmol) and using pyrrolidinein place of dibutylamine to produce 1.8 g (55% yield) of the titlecompound as the HCl salt, mp 229°-232° C. IR(KBr): 3400, 1600 cm⁻¹. MS:363(MH+). ¹H NMR (CD₃ OD): δ 7.91-6.87 (m, 10H), 4.04 (t, J=5.2 Hz, 2H),3.21 (m, 6H), 1.99 (m, 8H).

[0191] Theor. C₂₃H₂₆ N₂ O₂.HCl.H₂ O: C, 65.25; H, 7.01; N, 6.72. Found:C, 65.48; H, 7.24; N, 6.99.

EXAMPLE 10 E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole

[0192] The procedure of Example 1 was followed withp-hydroxybenzaldehyde (5.0 g, 41 mmol) and using 1-bromo-4-chlorobutane(9.5 ml, 82 mmol) in place of 1-bromo-3-chloropropane to give 8.9 g (97%yield) of 4-chlorobutoxybenzaldehyde. ¹H NMR (CDCl₃) δ 9.85 (s, 1H),7.82 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H),3.59 (t, J=5.3 Hz, 2H), 1.91 (m, 4H).

[0193] Condensation of this product (4.0 g, 19 mmol) with2-methylbenzoxazole (2.3 ml, 19 mmol) gave(E)-2-[2-(4-chlorobutoxyphenyl)ethenyl]benzoxazole (D) (4.5 g, 72%yield) as an off-white solid, mp 92°-93° C. ¹H NMR (CDCl₃): δ 7.88-6.81(m, 10H), 4.08 (t, J=5.1 Hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 2.55 (m, 4H).

[0194] Reaction of this product (3.0 g, 9.1 mmol) with dibutylamineproduced the named compound (0.4 g, 11% yield) which was converted tothe HCl salt, mp 172°-174° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 421(MH⁺). ¹HNMR (CD₃ OD): δ 7.82-6.85 (m, 10H), 4.02 (t, J=5.2 Hz, 2H), 3.11 (m,6H), 1.98-0.84 (m, 18H).

[0195] Theor. C₂₇H₃₆ N₂ O₂.HCl.H₂O: C, 68.26; H, 8.27; N, 5.6. Found: C,68.31; H, 7.91; N, 5.48.

EXAMPLE 11

[0196]

2-(4-Dipropylaminopropoxyphenyl)benzothiazole K_(i)=173 nM

[0197] The title compound was prepared as described in Example 43 ofU.S. Pat. No. 4,861,897 starting with (I) of Example 43 (2.0 g, 6.3mmol) and using dipropylamine in place of dibutylamine to produce 0.41 g(19% yield) of the title compound as the HCl salt, mp 142°-143° C.IR(KBr): 3400, 1600 cm⁻¹. MS: 369(MH⁺). ¹H NMR (CDCl₃): δ 8.19-6.95 (m,8H), 4.19 (t, J=5.1 Hz, 2H), 3.01 (m, 6H), 2.64-0.82 (m, 12H).

[0198] Theor. C₂₂H₂₈ N₂ OS.2HCl.1/2H₂ O: C, 58.65; H, 6.94; N, 6.22.Found: C, 58.55; H, 6.85; N, 6.17.

EXAMPLE 12

[0199]

(E)-2-[2-(3,5-Dimethyl-4-dipropylaminobutoxyphenyl)ethenyl]benzothiazoleK_(i)=1000 nM

[0200] The title compound was prepared according to the procedure ofExample 5 above using 4-chlorobutoxy-3, 5-dimethylbenzaldehyde in placeof 4-chlorobutoxybenzaldehyde and using 2-methylbenzothiazole in placeof 2-methylbenzoxazole. 4-Chlorobutoxy-3, 5-dimethylbenzaldehyde wasprepared from 3,5-dimethyl-4-hydroxybenzaldehyde according to theprocedure Example 1 above.

[0201] F. Biological Examples

[0202] In the present invention receptor binding was determined usingthe human histamine H₃ receptor (See Lovenberg et al Mol. Pharmacol.1999, 1107). Screening using the human receptor is particularlyimportant for the identification of new therapies for the treatment ofhuman disease. Conventional binding assays for example are determinedusing rat synaptosomes (Garbarg et al J. Pharmacol. Exp. Ther. 1992,263, 304), rat cortical membranes (West et al Mol. Pharmacol. 1990,610), and guinea pig brain (Korte et al Biochem. Biophys. Res. Commun.1990, 978). Only limited studies have been performed previously usinghuman tissue but these allude to significant differences in thepharmacology of rodent and primate receptors (West et al Eur. J.Pharmacol. 1999, 233).

BIOLOGICAL EXAMPLE 1

[0203] 1(A) Transfection of Cells with Human Histamine Receptor

[0204] A 10 cm tissue culture dish with a confluent monolayer of SK-N-MCcells was split two days prior to transfection. Using sterile techniquethe media was removed and the cells were detached from the dish by theaddition of trypsin. One fifth of the cells were then placed onto a new10 cm dish. Cells were grown in a 37° C. incubator with 5% CO₂ inMinimal Essential Media Eagle with 10% Fetal Bovine Serum. After twodays cells were approximately 80% confluent. These were removed from thedish with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One microgram supercoiled H₃ receptor CDNA wasadded to the cells and mixed. The voltage for the electroporation wasset at 0.25 kV, the capacitance is set at 960 μF.

[0205] After electroporation the cells were diluted into 10 mL completemedia and plated onto four 10 cm dishes. Due to the variability in theefficiency of electroporation, four different concentrations of cellswere plated. The ratios used were: 1:20, 1:10, and 1:5, with theremainder of the cells being added to the fourth dish. The cells wereallowed to recover for 24 hours before adding the selection media(complete media with 600 μg/ml G418). After 10 days dishes were analyzedfor surviving colonies of cells. Dishes with well-isolated colonies wereused. Cells from individual colonies were isolated and tested. SK-N-MCcells were used because they give efficient coupling for inhibition ofadenylate cyclase. The clones that gave the most robust inhibition ofadenylate cyclase in response to histamine were used for further study.

[0206] 1(B) [³H]-N-methylhistamine Binding

[0207] Cell pellets from histamine H₃ receptor-expressing SK-N-MC cellswere homogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatants from a 800 gspin were collected, reccentrifuged at 30,000 g for 30 minutes. Pelletswere rehomogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes wereincubated with 0.8 nM [³H]-N-methylhistamine plus/minus test compoundsfor 45 minutes at 25° C. and harvested by rapid filtration over GF/Cglass fiber filters (pretreated with 0.3% polyethylenimine) followed byfour washes with ice cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine accordingto Chen and Prusoff, Biochem. Pharmacol. 1973, 22:3099. K_(I) valueswere calculated based on a K_(D) of 800 pM and a ligand concentration([L]) of 800 pM according to the formula:

K_(I)=(IC₅₀)/(1+([L]/(K_(D))).

[0208] K_(I) values are provided in the examples above.

[0209] E. Other Embodiments

[0210] The features and advantages of the invention are apparent to oneof ordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

What is claimed is:
 1. A method for treating disorders mediated by thehistamine H₃ receptor in a patient, said method comprising administeringto the patient a pharmaceutically effective amount of compound offormula (I):

Ris O or S; R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, or I; R₂ and R₃are H or —O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃ is H and the otheris —O—(CH₂)_(m)—NR₄R₅, when R₃is —O—(CH₂)_(m)—NR₄R₅, R₂ is independentlyH, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy; R₄and R₅ are the same ordifferent, and are C₁₋₅ alkyl, C₃₋₆ cycloalkyl, benzyl, benzylsubstituted by c₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, I, or R₄ and R₅ togetherwith n are piperidyl, pyrrolidyl, imidazolyl, or n-substitutedpiperazyl, wherein the substituent is C₁₋₄ alkyl, phenyl, or phenylsubstituted with C₁₋₃ alkoxy; n is 0 or1; m is 2-6; with the provisosthat when at least one of R and R₁ is Ar; and both of R and R₁ are notAr; or a pharmaceutically acceptable salt, ester, or amide thereof.
 2. Amethod of claim 1 , wherein said condition is improved by administeringan H₃ antagonist.
 3. A method of claim 1 , wherein said compound has aformula wherein R₂ is H.
 4. A method of claim 1 , wherein said compoundhas a formula wherein R₃ is H.
 5. A method of claim 1 , wherein R is O.6. A method of claim 5 , wherein R₁ is H.
 7. A method of claim 1 ,wherein R is S.
 8. A method of claim 1 , wherein n is
 1. 9. A method ofclaim 1 , wherein said compound has a formula wherein NR₄R₅ is a cyclicradical.
 10. A method of claim 9 , wherein said cyclic radical ispiperidyl or pyrrolinyl.
 11. A method of claim 1 , wherein said compoundhas a formula wherein each of R₄ and R₅ is independently selected fromethyl, propyl, isopropyl, and butyl.
 12. A method of claim 1 , wherein mis 2, 3, or
 4. 13. A method of claim 12 , wherein m is
 3. 14. A methodof claim 1 , wherein R₁ is H, methyl, methoxy, Br, Cl, or I; each of R₄and R₅ is independently selected from ethyl, propyl, isopropyl, andbutyl, or together with N are piperidyl or pyrrolinyl; m is 3 or 4; andeach R₂ is H, halogen, methyl, or methoxy.
 15. A method of claim 1 ,wherein said compound is selected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole; and2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 16. A method of claim 1 ,wherein said compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole;.17. A method of claim 1 , wherein said compound is selected from(E)-2-[2-(4-d ibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl].
 18. A method ofclaim 1 , wherein said compound is selected from(E)-2-[2-(3-chloro4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylamino-propoxyphenyl)ethenyl]benzoxazole;and (E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl].
 19. Amethod for treating a patient with a central nervous system disorder,said method comprising administering to the patient apharmaceutically-effective amount of a compound of formula (I).
 20. Amethod of claim 19 , wherein said compound has a formula wherein R₁ isH, methyl, methoxy, Br, Cl, or I; each of R₄ and R₅ is independentlyselected from ethyl, propyl, isopropyl, and butyl, or together with Nare piperidyl or pyrrolinyl; m is 3 or 4; and each R₂ is H, halogen,methyl, or methoxy.
 21. A method of claim 19 , wherein said compound isselected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole;2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 22. A method of claim 19, wherein said central nervous system disorder is selected fromsleep/wake disorders, arousal/vigilance disorders, dementia, Alzheimer'sdisease, epilepsy, narcolepsy, eating disorders, motion sickness,vertigo, attention deficit hyperactivity disorder, learning and memorydisorders, mild cognitive impairment, and schizophrenia.
 23. A method ofclaim 19 , wherein said central nervous system disorder is selected fromAlzheimer's disease, epilepsy, eating disorders, learning and memorydisorders, migraine, sleep/wake disorders, allergic rhinitis,schizophrenia, mild cognitive impairment, and asthma.
 24. A method ofclaim 19 , wherein said disorder is selected from sleep/wake disorders,arousal/vigilance disorders, attention deficit hyperactivity disorder,and learning and memory disorders.
 25. A method of claim 19 , whereinsaid compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole.26. A method of claim 19 , wherein said compound is selected from(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methyl-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxy-benzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl].
 27. A method ofclaim 19 , wherein said compound is selected from(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxy-phenyl)ethenyl]benzoxazoleand(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole.28. A method for treating a patient with an upper airway allergicresponse, said method comprising administering to the patient apharmaceutically-effective amount of a compound of formula (I).
 29. Amethod of claim 28 , wherein R₁ is H, methyl, methoxy, Br, Cl, or I;each of R₄ and R₅ is independently selected from ethyl, propyl,isopropyl, and butyl, or together with N are piperidyl or pyrrolinyl; mis 3 or 4; and each R₂ is H, halogen, methyl, or methoxy.
 30. A methodof claim 28 , wherein said compound is selected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole;2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 31. A method of claim 28, wherein said compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole.32. A method of claim 28 , wherein said compound is selected from(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxy-phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminopropoxy-phenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-d iethylaminobutoxyph enyl )ethenyl] be nzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole.
 33. Amethod of claim 28 , wherein said compound is selected from(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)-ethenyl]benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;and(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole.